The Effect of Exercise on Cardiotoxicity in Women with Breast Cancer Receiving Anthracycline-Based Chemotherapy: A Systematic Review and Meta-Analysis.

INTRODUCTION: Breast cancer is the most common cancer in women with a 5-year survival over 90%. However, anthracycline-based chemotherapy causes significant cardiotoxicity often requiring discontinuation of chemotherapeutic regimen among breast cancer survivors. We conducted a systematic review and meta-analysis to evaluate the efficacy of exercise training in mitigating anthracycline-related cardiotoxicity among women with breast cancer. METHODS: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases. The outcomes of interest were left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), early to atrial filling velocity (E/A) ratio, maximal oxygen consumption (VO2 max), and cardiac output (CO). We used the Cochrane risk-of-bias tool for randomized trials (RoB 2) to assess the risk of bias in individual studies. RESULTS: We identified a total of 596 articles with 5 trials included in the final analysis. Exercise training was associated with an increase in VO2 max compared with no exercise training (mean difference, 3.95 [95% CI, 0.63-7.26]; I2 = 99.68%). Other cardiovascular outcomes such as LVEF (mean difference, 1.76 [95% CI, -1.95 to 5.46]; I2 = 99.44%), GLS (mean difference, 0.30 [95% CI, -0.49 to 1.10]; I2 = 96.63%), E/A ratio (mean difference, 0.05 [95% CI, -0.05 to 0.15]; I2 = 94.16%), and CO (mean difference, 0.38 [95% CI, -0.91 to 1.66]; I2 = 99.73%) are similar between patients who underwent exercise training and those who did not. CONCLUSIONS: Exercise was associated with an improvement in maximal oxygen uptake among women with breast cancer receiving anthracycline-based chemotherapy.

The impact of sodium-glucose cotransporter-2 inhibitors on outcome of patients with diabetes mellitus and colorectal cancer.

BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) have a higher risk of colorectal cancer (CRC), and those with diagnosed CRC have a poorer prognosis compared with individuals with normal glucose levels. The inhibition of sodium-glucose cotransporter 2 (SGLT2) channels has been associated with a reduction in tumor proliferation in preclinical studies. We aimed to investigate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcome of T2DM patients with colorectal cancer. METHODS: We performed a retrospective cohort study comprising adult patients with T2DM and colorectal adenocarcinoma. SGLT2i recipients were matched to non-SGLT2i recipients in a 1:1 ratio based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with SGLT2i. RESULTS: We identified 1347 patients with T2DM and colorectal adenocarcinoma, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of 5-year OS (86.2% [95% CI: 72.0-93.5] vs 62.3% [95% CI: 50.9-71.8], P = 0.013) and 5-year PFS (76.6% [95% CI: 60.7-86.7] vs 57.0% [95% CI: 46.2-66.4], P = 0.021). In Cox proportional hazard analyses, SGLT2i were associated with a 50-70% reduction in all-cause mortality and disease progression. SGLT2i were not associated with an increased risk of serious adverse events. CONCLUSION: SGLT2i were associated with a higher rate of survival in T2DM patients with colorectal cancer.

Thromboprophylaxis for outpatients with COVID-19: a Systematic Review and Meta-analysis.

Patients with COVID-19 develop an increased risk of thromboembolism. Thromboprophylaxis is recommended for hospitalized COVID-19 patients, but the role of thromboprophylaxis in outpatients with COVID-19 is less well defined. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of thromboprophylaxis among outpatients with COVID-19. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to August 2023. The outcomes of interest were venous thromboembolic events including deep venous thrombosis and pulmonary embolism, all-cause mortality, cardiovascular events, hospitalization, major bleeding events, and non-major bleeding events. We included 6 trials comprising 3352 patients. Patients who received thromboprophylaxis had an approximately 70% reduction in venous thromboembolism (RR, 0.28 [95% CI, 0.08 to 0.93]) compared to patients who did not receive thromboprophylaxis. The risk of mortality (RR, 0.79 [95% CI, 0.35 to 1.77]), cardiovascular events (RR, 0.91 [95% CI, 0.30 to 2.73]), and hospitalization (RR, 1.09 [95% CI, 0.81 to 1.47]) were similar between the two groups. Patients who received thromboprophylaxis had a higher risk of non-major bleeding (RR, 3.48 [95% CI, 1.72 to 7.05) compared to patients who did not receive thromboprophylaxis. Thromboprophylaxis reduced the risk of venous thromboembolism but not mortality, cardiovascular events, or hospitalization among outpatients with COVID-19.

Effect of metformin on outcomes of patients treated with immune checkpoint inhibitors: a retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape of cancer treatment, but only a fraction of patients responds to treatment, leading to an increasing effort to repurpose clinically approved medications to augment ICI therapy. Metformin has been associated with improved survival outcomes in patients undergoing conventional chemotherapy. However, whether metformin provides survival benefits in patients receiving immune checkpoint inhibitors (ICIs) is unknown. METHODS: We performed a retrospective cohort study at two tertiary referral centers in Taiwan. All adult diabetes mellitus patients who were treated with ICIs between January 2015 and December 2021 were included. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: In total, 878 patients were enrolled in our study, of which 86 patients used metformin and 78 patients used non-metformin diabetes medications. Compared with non-users, metformin users had a longer median OS (15.4 [IQR 5.6-not reached] vs. 6.1 [IQR, 0.8-21.0] months, P = 0.003) and PFS (5.1 [IQR 2.0-14.3] vs. 1.9 [IQR 0.7-8.6] months, P = 0.041). In a univariate Cox proportional hazard analysis, the use of metformin was associated with a reduction in the risk of mortality (HR: 0.53 [95% confidence interval: 0.35-0.81], P = 0.004) and disease progression (HR: 0.69 [95% CI 0.49-0.99], P = 0.042). The use of metformin remained associated with a lower risk of mortality after adjusting for baseline variables such as age, cancer stage, and underlying comorbidities (OS, HR: 0.55 [95% CI 0.34-0.87], P = 0.011). Similarly, the use of metformin was associated with a lower risk of disease progression. Importantly, the use of metformin before ICI initiation was not associated with a reduction in mortality (HR: 0.61 [95% CI 0.27-1.42], P = 0.25) or disease progression (HR: 0.69 [95% CI 0.33-1.43], P = 0.32). CONCLUSION: The use of metformin is associated with survival benefits in patients undergoing immunotherapy. Prospective clinical trials are warranted to define the role of metformin in augmenting immunotherapy.

Efficacy of Lipophilic Statins on Outcomes of Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Statins are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the impact of lipophilic and hydrophilic statin properties on patient outcomes is unknown. OBJECTIVES: We aim to investigate if statins with lipophilic properties are associated with clinical outcomes in patients receiving ICIs. METHOD: We conducted a retrospective cohort study at two tertiary referral centers in Taiwan comprising patients receiving ICIs between January 2015 and December 2021. We compared the comparative effect of lipophilic and hydrophilic statins on patient outcomes. The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). RESULTS: Among 734 patients receiving ICIs, there were 51 lipophilic statin users, 25 hydrophilic statin users, and 658 nonusers. Lipophilic statin users had a longer median OS (38.0 [IQR, 16.7-not reached] vs. 15.2 [IQR, 8.2-not reached] months vs. 18.9 [IQR, 5.4 51.6] months) and PFS (13.0 [IQR, 4.7-41.5] vs. 8.2 [IQR, 2.2-14.7] months vs. 5.6 [2.3-18.7] months) than hydrophilic statin users and non-statin users. In Cox proportional hazard analyses, the use of lipophilic statins was associated with a 40-50% lower risk of mortality and disease progression compared with hydrophilic statin or non-statin users. CONCLUSIONS: The use of lipophilic statins seems to be associated with survival benefits in patients undergoing immunotherapy.

The incidence and risk of cardiovascular events associated with immune checkpoint inhibitors in Asian populations.

OBJECTIVES: Immune checkpoint inhibitors are associated with adverse cardiovascular events. However, there are no data characterizing cardiovascular events among Asians on immune checkpoint inhibitors. We aim to determine the incidence and risk of cardiac events associated with immune checkpoint inhibitors in an Asian population. METHODS: We performed a retrospective, propensity score-matched cohort study at two tertiary referral centers in Taiwan. Immune checkpoint inhibitor users were matched with non-immune checkpoint inhibitor users based on predetermined clinical variables. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, ischemic stroke, acute peripheral occlusive disease, pulmonary embolism, deep venous thrombosis, heart failure, pericardial disease, myocarditis, cardiac arrhythmias and conduction block. RESULTS: Between January 2010 and November 2021, 868 immune checkpoint inhibitor users were matched 1:1 with non-immune checkpoint inhibitor users. Among immune checkpoint inhibitor users, 67 (7.7%) patients developed major adverse cardiovascular events. During a median follow-up period of 188 days, the incidence rate of major adverse cardiovascular events for immune checkpoint inhibitor and non-immune checkpoint inhibitor users was 94.8 and 46.2 per 1000 patient-years, respectively, resulting in an incidence rate ratio of 2.1 [95% confidence interval: 1.5-2.9]. In multivariate Cox proportional hazard models, immune checkpoint inhibitor users had a 60% increased risk for major adverse cardiovascular events [hazard ratio, 1.6 (95% confidence interval: 1.1-2.3)]. Immune checkpoint inhibitors use was independently associated with increased risk of ischemic stroke [hazard ratio, 3.0 (95% confidence interval: 1.0-9.0)] and pulmonary embolism [hazard ratio, 5.5 (95% confidence interval: 1.4-21.3)]. In multivariate logistic regression analysis, age > 65, metastatic disease, hypertension and baseline platelet-to-lymphocyte ratio < 180 were risk factors for major adverse cardiovascular events. CONCLUSIONS: Among Asians, immune checkpoint inhibitors were associated with an increased risk of major adverse cardiovascular events, particularly ischemic stroke and pulmonary embolism.

Reduced-port robotic pancreaticoduodenectomy versus open pancreaticoduodenectomy: a single-surgeon experience.

BACKGROUND AND OBJECTIVES: Multiple-port robotic pancreaticoduodenectomy (RPD) has been increasingly used as an alternative to open pancreaticoduodenectomy (OPD) in pancreatic cancer. However, the comparative safety and efficacy of reduced-port RPD versus OPD are unknown. METHODS: This was a prospective cohort study comprising adult patients who underwent reduced-port RPD (single-port or single-site plus one port) or OPD for malignant tumors of the pancreas and periampullary region from July 2015 to October 2020 at a single center. We collected data on the patient demographics, perioperative results, oncologic outcomes, and one-year survival. RESULTS: Forty-five patients underwent reduced-port RPD, and 13 underwent OPD. There were no significant differences in the age, sex, body mass index, ASA score, tumor location, or occurrences of postoperative complications between the two groups. Compared with OPD, reduced-port RPD was associated with less blood loss (300 ml [95% confidence interval {CI} 155-700] vs. 650 ml [95% CI 300-850], p value = 0.11) but a longer operative time (325 min [95% CI 290-370] vs. 215 min [95% CI 180-270], p value < 0.001). Compared with patients who underwent OPD, patients who underwent reduced-port RPD had a higher 1-year survival rate (68% [95% CI 49-81] vs. 22% [95% CI 3-51], log-rank, p value = 0.007). CONCLUSIONS: Reduced-port RPD can be safely performed in experienced surgeons and is associated with better perioperative and oncologic outcomes than OPD.

Impact of different corticosteroids on severe community-acquired pneumonia: a systematic review and meta-analysis.

OBJECTIVES: Randomised controlled trials (RCTs) have demonstrated conflicting results regarding the effects of corticosteroids on the treatment of severe community-acquired pneumonia (CAP). We aimed to investigate the efficacy and safety of different corticosteroids on patients who were hospitalised for severe CAP. METHODS: We performed a systematic search through PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to May 2023. The primary outcome was all-cause mortality. Data analysis was performed using a random-effects model. RESULTS: A total of 10 RCTs comprising 1962 patients were included. Corticosteroids were associated with a lower rate of all-cause mortality (risk ratio (RR), 0.70 (95% CI 0.54 to 0.90); I2=0.00%). When stratified into different corticosteroid types, hydrocortisone was associated with an approximately 50% lower mortality risk (RR, 0.48 (95% CI 0.32 to 0.72); I2=0.00%). However, dexamethasone, methylprednisolone or prednisolone were not associated with an improvement in mortality. Furthermore, hydrocortisone was associated with a reduction in the rate of mechanical ventilation, acute respiratory distress syndrome, shock and duration of intensive care unit stay. These trends were not observed for dexamethasone, methylprednisolone or prednisolone. Corticosteroids were not associated with an increased risk of adverse events including gastrointestinal bleeding, secondary infection or hyperglycaemia. CONCLUSIONS: The use of hydrocortisone, but not other types of corticosteroids, was associated with a reduction in mortality and improvement in pneumonia outcomes among patients hospitalised with severe CAP.PROSPERO registration numberCRD42023431360.

Periodontitis is an immune-related adverse event associated with immune checkpoint inhibitors: A multi-center cohort study.

Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) across various organ systems including oral health complications such as dry mouth and stomatitis. In this study, we aimed to determine the risk of periodontitis among patients on immune checkpoint inhibitors (ICIs) and to test the associations between ICI-associated periodontitis and other immune-related adverse events (irAEs). We performed a retrospective cohort study involving adult cancer patients between January 2010 and November 2021. Patients on an ICI were propensity score-matched to patients not on an ICI. The primary outcome was the occurrence of periodontitis. ICIs included programmed cell death 1 (PD-1) inhibitors programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. The risk of periodontitis following ICI use was derived through a Cox proportional hazard model and Kaplan-Meier survival analysis. Overall, 868 patients on an ICI were matched to patients not on an ICI. Among the ICI cohort, 41 (4.7%) patients developed periodontitis. The incidence rate of periodontitis was significantly higher in patients on an ICI than in patients not on an ICI (55.3 vs 25.8 per 100 patient-years, incidence rate ratio=2.14, 95% CI=1.38-3.33). Both the use of PD-L1 inhibitors (multivariate HR=2.5, 95%CI=1.3-4.7) and PD-1 inhibitors (multivariate HR=2.0, 95%CI=1.2-3.2) were associated with the risk of periodontitis. The presence of immune-related periodontitis was associated with better overall survival (not reached vs 17 months, log-rank p-value<0.001), progression-free survival (14.9 vs 5.6 months, log-rank p-value=0.01), and other concomitant immune-related cutaneous adverse events. In conclusion, ICI was associated with an increased risk of periodontitis. Immune-related periodontitis as an irAE was associated with better cancer survival and concomitant cutaneous irAEs.

The Efficacy of Cationic Amphiphilic Antihistamines on Outcomes of Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Cationic amphiphilic H1-antihistamines have demonstrated antitumor effects in preclinical studies. We conducted a retrospective cohort study to investigate their impact on patients with pancreatic adenocarcinoma (PDAC). METHODS: We performed a matched cohort study involving PDAC patients from two tertiary centers in Taiwan using criteria including age, sex, and cancer stage. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and objective response rates (ORR). RESULTS: We matched 28 cationic amphiphilic antihistamine users with 56 non-cationic amphiphilic antihistamine users. Cationic amphiphilic antihistamine users showed significantly longer OS (median 16.4 [IQR, 2.8 - 89.0] vs.5.8 [IQR, 2.0 - 9.8] months; p<0.001) and PFS (median 12.2 [IQR, 2.2 - 83.3] vs. 5.2 [IQR, 1.7 - 8.4] months; p=0.002) compared to non-users. In the Cox proportional hazard models, the use of cationic amphiphilic antihistamines was associated with approximately 60% lower risk of all-cause mortality and disease progression. Additionally, cationic amphiphilic antihistamine users exhibited a significantly greater ORR than non-users (39% vs. 7%, p=0.004). CONCLUSION: Our study suggests that cationic amphiphilic antihistamines are associated with improved survival outcomes in PDAC patients.

The relationship between statin administration timing and survival outcomes in patients with cancer receiving immune checkpoint blockade.

OBJECTIVE: Statins have been demonstrated to improve outcomes in patients receiving immune checkpoint blockade (ICB). This study aimed to investigate whether the timing of statin administration influences the outcomes of patients receiving ICB. METHODS: We conducted a retrospective cohort study utilizing electronic health records from two tertiary referral centers in Taiwan. We compared the overall survival (OS) and progression-free survival (PFS) of patients who received statins before and after ICB initiation. RESULTS: We included 734 patients who received ICB. Among them, 606 were non-statin users, 76 started statins after ICB initiation, and 52 started statins before ICB initiation. Post-ICB statin users demonstrated significantly prolonged OS (median 37.6 versus 10.3 versus 11.3 months, p = 0.009) and PFS (median 10.5 versus 6.3 versus 5.6 months, p = 0.024) compared to pre-ICB statin and non-statin users. Statin use after ICB initiation had a reduced risk of all-cause mortality (HR, 0.65 [95% CI: 0.45-0.94], p = 0.022) and progressive disease (HR, 0.71 [95% CI: 0.53-0.95], p = 0.021) by approximately 30-35%, compared to non-statin users. However, statin use prior to ICB initiation did not affect the risk of all-cause mortality or progressive disease. Similar results were observed after controlling for potential cofounders such as age, sex, cancer stage, and cancer type. CONCLUSIONS: These findings suggest that initiating statin therapy after the initiation of ICB, regardless of indication, is associated with improved patient prognosis.

The impact of peroxisome proliferator-activated receptor-γ activating angiotensin receptor blocker on outcomes of patients receiving immunotherapy.

BACKGROUND: Certain angiotensin receptor blockers (ARBs) have peroxisome proliferator-activated receptor-γ (PPAR-γ) activation property, which has been associated with improved programmed cell death ligand 1 blockade and cytotoxic T lymphocyte-mediated antitumor activity. METHODS: We conducted a retrospective cohort study to investigate the impact of PPAR-γ-activating ARBs on patient survival in patients treated with immune checkpoint inhibitors (ICIs) across all types of cancers. RESULTS: A total of 167 patients receiving both angiotensin receptor blockers (ARBs) and immune checkpoint inhibitors (ICIs) were included. Compared with non-PPAR-γ-ARB users (n = 102), PPAR-γ-ARB users (n = 65) had a longer median overall survival (not reached [IQR, 16.0-not reached] vs. 18.6 [IQR, 6.1-38.6] months) and progression-free survival (17.3 [IQR, 5.1-not reached] vs. 8.2 [IQR, 2.4-18.6] months). In Cox regression analysis, the use of PPAR-γ-activating ARBs had an approximately 50% reduction in all-cause mortality and disease progression. Patients who received PPAR-γ-activating ARBs also had higher clinical benefit rates than non-PPAR-γ-ARB users (82% vs. 61%, p = 0.005). CONCLUSION: The use of ARBs with PPAR-γ-activating property is linked with better survival among patients receiving ICIs.

Impact of sodium-glucose cotransporter-2 inhibitors on heart failure and mortality in patients with cancer.

OBJECTIVES: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce heart failure (HF) in at-risk patients and may possess antitumour effects. We examined the effect of SGLT2i on HF and mortality among patients with cancer and diabetes. METHODS: This was a retrospective propensity score-matched cohort study involving adult patients with type 2 diabetes mellitus diagnosed with cancer between January 2010 and December 2021. The primary outcomes were hospitalisation for incident HF and all-cause mortality. The secondary outcomes were serious adverse events associated with SGLT2i. RESULTS: From a total of 8640 patients, 878 SGLT2i recipients were matched to non-recipients. During a median follow-up of 18.8 months, SGLT2i recipients had a threefold lower rate of hospitalisation for incident HF compared with non-SGLT2i recipients (2.92 vs 8.95 per 1000 patient-years, p=0.018). In Cox regression and competing regression models, SGLT2i were associated with a 72% reduction in the risk of hospitalisation for HF (HR 0.28 (95% CI: 0.11 to 0.77), p=0.013; subdistribution HR 0.32 (95% CI: 0.12 to 0.84), p=0.021). The use of SGLT2i was also associated with a higher overall survival (85.3% vs 63.0% at 2 years, p<0.001). The risk of serious adverse events such as hypoglycaemia and sepsis was similar between the two groups. CONCLUSIONS: The use of SGLT2i was associated with a lower rate of incident HF and prolonged overall survival in patients with cancer with diabetes mellitus.

Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors.

BACKGROUND: Cationic amphiphilic antihistamines have been shown to improve patient outcomes in immunogenic tumours, but whether they can augment and improve response to immunotherapy is unknown. We aim to evaluate the effect of cationic amphiphilic antihistamines in patients receiving immune checkpoint inhibitors (ICIs). METHODS: We conducted a retrospective propensity score-matched cohort study at two tertiary referral centres in Taiwan between January 2015 and December 2021. Patients who received desloratadine, cyproheptadine, and ebastine were classified as cationic amphiphilic antihistamine users. The primary outcome was overall survival, and the secondary outcomes were progression-free survival and clinical benefit rate. Patients treated with cationic amphiphilic antihistamines were matched to patients who received non-cationic amphiphilic antihistamines based on variables including age, cancer type, stage, and history of allergic diseases. RESULTS: A total of 734 ICI-treated patients were included. After matching, 68 cationic amphiphilic antihistamine and non-cationic amphiphilic antihistamine users remained for analysis. Compared with non-cationic amphiphilic antihistamine users, patients who received cationic amphiphilic antihistamines had a significantly longer median overall survival (24.8 versus 10.4 months; Log-rank, p = 0.018) and progression-free survival (10.6 versus 4.93 months; Log-rank, p = 0.004). The use of cationic amphiphilic antihistamines was associated with an approximately 50% lower risk of all-cause mortality (HR, 0.55 [95% CI: 0.34-0.91]). Survival benefits were not seen in patients who received cationic amphiphilic antihistamines before immune checkpoint blockade. These survival benefits were observed regardless of the generation of cationic amphiphilic antihistamines. CONCLUSION: The use of cationic amphiphilic antihistamines was associated with improved survival among patients treated with immunotherapy.